Rabeximod in the treatment of rheumatoid arthritis

ABSTRACT

The present invention relates to therapeutic uses of compositions comprising 9-Chloro-2,3-dimethyl-6-(N,N-dimethylaminoethylamino-2-oxoethyl)-6H-indolo-[2,3-b]quinoxaline in the treatment of human subjects suffering from Rheumatoid Arthritis.

TECHNICAL FIELD

The present invention relates to therapeutic uses of compositionscomprising9-Chloro-2,3-dimethyl-6-(N,N-dimethylaminoethylamino-2-oxoethyl)-6H-indolo-[2,3-b]quinoxaline(rabeximod) in the treatment of rheumatoid arthritis. The presentinvention further relates to oral composition comprising a crystallineform of9-Chloro-2,3-dimethyl-6-(N,N-dimethylaminoethylamino-2-oxoethyl)-6H-indolo-[2,3-b]quinoxaline(rabeximod) that are particularly suitable for use in these treatments.

BACKGROUND ART

The compound rabeximod has been described in European patent applicationpublication EP1756111A1 and its US counterpart US 2005/288296. Thepreparation of rabeximod is specifically described in these patentpublications, as compound E. The process described is a small-scaleprocess without any description on how to make a process that can beused for GMP and up scaled. The compound rabeximod was not isolated as asolid.

EP1756111 and US 2005/288296 describe initial tests of rabeximod(compound E) in animal models for rheumatoid arthritis and multiplesclerosis.

The objective of the present invention is to provide efficacioustreatments of subjects suffering from rheumatoid arthritis. A furtherobjective of the present invention is to provide formulations that cansuitably be used to administer therapeutically effective dosages ofrabeximod in these (and other) methods of treatment.

SUMMARY OF THE INVENTION

The invention, generally stated, concerns new and improved formulationscontaining rabeximod or a salt thereof as well as new treatments anddosage regimens using rabeximod in the rheumatoid arthritis therapeuticarea.

Specific objects and advantages of these formulations, treatments anddosage regimens will appear from the following description, and claims.

DESCRIPTION OF THE INVENTION

The compound known under the INN ‘rabeximod’ has the IUPAC name9-Chloro-2,3-dimethyl-6-(N,N-dimethylaminoethylamino-2-oxoethyl)-6H-indolo-[2,3-b]quinoxalineand has the following molecular structure.

The preparation of Rabeximod is described in EP1756111A1 andUS2005/288296. Throughout the present application, the terms“Rabeximod”, “rabeximod” and“9-Chloro-2,3-dimethyl-6-(N,N-dimethylaminoethylamino-2-oxoethyl)-6H-indolo-[2,3-b]quinoxaline”are used interchangeably and mean the compound in any solid form orliquid form unless otherwise indicated or implied under the givencircumstances.

Compositions

In a first aspect the present invention relates to a solid oralcomposition comprising a crystalline form of9-Chloro-2,3-dimethyl-6-(N,N-dimethylaminoethylamino-2-oxoethyl)-6H-indolo-[2,3-b]quinoxaline(Rabeximod) or a pharmaceutically acceptable salt thereof and optionallya pharmaceutically acceptable additive.

The pharmaceutically acceptable additive is typically present and isselected from one or more of a filler, glidant, and lubricant, as longas the additive do not affect stability of the rabeximod. Typical filleris Microcrystalline cellulose (Avicel PH-102) or (Avicel PH-200).Typical glidant is Silica colloidal anhydrous (Aerosil 200). Typicallubricant is Magnesium stearate.

In a further embodiment rabeximod is a crystalline free base.Preferably, the rabeximod is a crystalline free base having a meltingpoint of 259-261° C.

In a still further embodiment the composition comprises rabeximod in theform of a dry powder, e.g. a micronized powder. The particle sizedistribution can be determined by means of laser diffractometry. In apreferred embodiment, a Malvern Instruments Mastersizer is used todetermine the particle size distribution. Using a Malvern Mastersizerapparatus, volume-based size distribution parameters will typically bereported, e.g. in the form of the D10, D50 and D90 values. The averageparticle size (D50-value), which is also denoted D50-value of theintegral volume distribution, is defined in the context of thisinvention as the particle diameter at which 50 percent by volume of theparticles have a smaller diameter than the diameter which corresponds tothe D50-value. Likewise, 50 percent by volume of the particles have alarger diameter than the D50-value. Analogously, the D90-value of theintegral volume distribution is defined as the particle diameter atwhich 90 percent by volume of the particles have a smaller diameter thanthe diameter which corresponds to the D90-value. Correspondingly, theD10-value of the integral volume distribution is defined as the particlediameter at which 10 percent by volume of the particles have a smallerdiameter than the diameter which corresponds to the D10-value.Typically, the rabeximod dry powder has a particle size characterized bya D10 within the range of 0.5-1.0 μm, a D50 within the range of 1.5-3.5μm, and/or a D90 within the range of 5.5-9.9 μm, when measured usinglaser light diffractometry.

In accordance with the various aspects of the invention, the compositionis preferably provided in the form of a unit dosage form. The term ‘unitdosage form’ refers to a physically discrete unit suitable as a unitarydosage for human subjects, each unit containing a predetermined quantityof active material calculated to produce the desired therapeutic effectin association with any suitable pharmaceutical carrier(s) and/orexcipient(s). Exemplary, non-limiting unit dosage forms include a tablet(e.g., a chewable tablet), caplet, capsule (e.g., a hard capsule or asoft capsule), etc. In accordance with the invention, the unit dosageform, is a unit dosage form that is suitable for oral administration.Most preferably, it is a solid unit dosage form, such as a tablet orcapsule, most preferably a capsule, such as a standard gelatin capsule,which is filled with a powder as defined herein.

It is preferred that the solid oral composition of the present inventionis an immediate release (IR) composition. Even more preferred in the IRcomposition of the present invention at least 70% of the rabeximod isdissolved within 45 minutes in a mammalian subject, such as a human.More preferred, at least 90% of the rabeximod is dissolved within 45minutes in a mammalian subject, such as a human. Optimally, at least 90%of the rabeximod is dissolved within 15 minutes in a mammalian subject,such as a human.

Even more preferred in the IR composition of the present invention atleast 70% of the rabeximod is dissolved within 45 minutes in astandardized in vitro dissolution test. More preferred, at least 90% ofthe rabeximod is dissolved within 45 minutes in a standardized in vitrodissolution test. Optimally, at least 90% of the rabeximod is dissolvedwithin 15 minutes in a standardized in vitro dissolution test. Unlessspecified otherwise in this document, in vitro dissolution testing ofthe solid oral composition is carried out in a so called USP dissolutionapparatus II at a temperature of 37° C. and a rotational speed of thepaddle of 50 to 75 RPM. For investigating the release profile, simulatedgastric fluid, typically in an amount of 500 to 900 ml, is used, whichhas the following composition: sodium lauryl sulphate 2.5 g; sodiumchloride 2.0 g; 0.01-0.05 N hydrochloric acid in water 1000 ml. Activeingredient concentrations in the dissolution medium can be determined byany suitable analytical method, like ultraviolet absorption or HPLCanalysis.

In a further aspect the present invention concerns a solid oral unitdosage form, such as a capsule or tablet as defined herein, comprisingrabeximod in an amount of at least at least 1 mg, more preferably atleast 2 mg, at least 4 mg, at least 6 mg, at least 8 mg, at least 10 mg,at least 12 mg, at least 13 mg, at least 14 mg, or at least 15 mg and/orin an amount of 500 mg or less, more preferably 250 mg or less, 100 mgor less, 75 mg or less, 50 mg or less, 40 mg or less, 30 mg or less, 25mg or less or 20 mg or less; or a salt of rabeximod in the equipotentdosage. As used herein, the term “equipotent” means equally potent orequally capable of producing a pharmacologic effect of certainintensity. For example, if the composition comprises a salt of rabeximodthe amount of said salt to be administered typically needs to beadjusted to take account of the molecular weight difference between thefree base and salt form. It is also common in the art to refer toamounts of a given compound “equivalent” to a specified amount of areference compound. For instance, in expressing dose amounts in thelabel and/or product information of authorized medicinal productscomprising a salt form of an active compound that can also be used infree base form, it is customary practice to specify the dose of the freebase that the dose of the salt is equivalent to. In this context, theterm ‘equipotent’ is deemed synonymous to the term ‘equivalent’. Inpreferred embodiments, a solid oral unit dosage form as defined hereinis provided, comprising rabeximod in an amount within the range of 5-25mg, 10-20 mg, 12-18 mg, 13-17 mg, or 14-16 mg, e.g. in an amount ofabout 15 mg; or a salt of rabeximod in the equipotent/equivalent amount.In certain preferred embodiments, a solid oral unit dosage form asdefined herein is provided, comprising rabeximod in an amount of 10, 11,12, 13, 14, 15, 16, 17, 18, 19 or 20 mg; or a salt of rabeximod at theequipotent/equivalent amount.

In an embodiment the solid oral unit dosage form is a capsule comprisinga dosage selected from any one of 6.25 mg, 12.5 mg, 15 mg, 25 mg, 37.5mg, or 50 mg. Preferably the capsule comprises a dosage of rabeximod of15 mg. Any one of these unit dosage form comprising rabeximod may beadministered daily to treat rheumatoid arthritis in a human subject,such a solid oral unit dosage form comprising rabeximod in an amount of15 mg per unit dosage, preferably this is administered once daily.

Methods of Treatment

In a broad aspect, the present invention relates to methods of treatinga subject in need thereof, in particular a subject suffering from and/ordiagnosed with rheumatoid arthritis, or a related condition, said methodcomprising administering to said subject, a composition comprisingRabeximod or a pharmaceutically acceptable salt thereof, preferably asolid oral composition as defined herein before.

In preferred embodiments of the invention, the subject to be treated isa human subject, preferably a human subject suffering from rheumatoidarthritis, preferably moderate rheumatoid arthritis, severe rheumatoidarthritis or moderate to severe rheumatoid arthritis.

In an embodiment the subject to be treated is a human subject sufferingfrom rheumatoid arthritis of global functional status class I, II orIII, according to the criteria developed by the American College ofRheumatoid Arthritis. In an embodiment the subject to be treated is ahuman subject suffering from rheumatoid arthritis of global functionalstatus class of II, III or IV, in particular III or IV.

In an embodiment the subject to be treated is a human subject sufferingfrom rheumatoid arthritis and having a Central laboratory C-reactiveprotein (CRP) level of at least 1.5 mg/dL.

In some preferred embodiments of the invention, the subject is a poorresponder or non-responder to other pharmacological therapies, such astreatment with methotrexate. In some embodiments, the subject hasundergone methotrexate treatment for a period of at least 5, at least10, at least 15 or at least 20 weeks, without showing significant and/orsufficient response to said treatment or without showing any response tosaid treatment.

In some embodiments, the subject is a human subject that is consideredat increased risk of developing rheumatoid arthritis, e.g. because orgenetic predisposition. In some embodiments, the subject is a humansubject having one or more genetic markers indicative of increased riskof developing rheumatoid arthritis. In some embodiments, the subject isa human subject having a biomarker profile indicative of increased riskof developing rheumatoid arthritis. In certain embodiments, the presentmethods comprise the step of identifying subjects that are at increasedrisk of developing rheumatoid arthritis. In certain embodiments, thepresent methods comprise the step of diagnosing or establishing whethera subject is at increased risk of developing arthritis.

In preferred embodiments, the present method is a method of treatingrheumatoid arthritis, delaying the progression of rheumatoid arthritis,stopping or preventing the progression of rheumatoid arthritis, inducingremission of rheumatoid arthritis, delaying the onset of rheumatoidarthritis or preventing the onset of rheumatoid arthritis.

In further preferred embodiments, the present method is a method oftreating a symptom of rheumatoid arthritis, delaying the progression ofa symptom of rheumatoid arthritis, stopping or preventing theprogression of a symptom of rheumatoid arthritis, inducing remission ofa symptom of rheumatoid arthritis, delaying the onset of a symptom ofrheumatoid arthritis or preventing the onset of a symptom rheumatoidarthritis. Said symptom is preferably selected from the group consistingof tender, warm and/or swollen joints; joint stiffness, particularly inthe morning and after periods of inactivity, and symptoms not involvingjoints, such as fatigue and symptoms involving any of the skin, eyes,lungs, heart, kidneys, salivary glands, nerve tissue, bone marrow andblood vessels. In particularly preferred embodiments, said symptom is asymptom involving a joint, in particular the joints attaching thefingers to the hand, the joints attaching the toes to the feet, thewrits, the ankles, the elbows, the hips and/or the shoulders.

In a particularly preferred embodiment, the method achieves an ACR20response. As used herein, the abbreviation ‘ACR’ refers to the AmericanCollege of Rheumatology (ACR) core set of disease activity measures. AnACR20 response is defined as at least 20% improvement in both the tenderjoint count and the swollen joint count and at least 20% improvement in3 of the following core set measures: physician's assessment of diseaseactivity, patient's assessment of disease activity, patient's assessmentof pain, and patient's assessment of physical function, and levels of anacute-phase reactant (either the C-reactive protein [CRP] level or theerythrocyte sedimentation rate [ESR]). In a particularly preferredembodiment, the method achieves an ACR20 response within e.g. 10-24weeks of treatment, within 12-20 weeks of treatment, or within 14-18weeks of treatment.

In a particularly preferred embodiment, the method achieves an ACR50response. In a particularly preferred embodiment, the method achieves anACR50 response within e.g. 10-24 weeks of treatment, within 12-20 weeksof treatment, or within 14-18 weeks of treatment.

In a particularly preferred embodiment, the method achieves an ACR70response. In a particularly preferred embodiment, the method achieves anACR70 response within e.g. 10-24 weeks of treatment, within 12-20 weeksof treatment, or within 14-18 weeks of treatment.

In a particularly preferred embodiment, the method achieves a decreasefrom baseline in DAS28 score. The DAS28 is a measure of disease activityin rheumatoid arthritis (RA). DAS stands for ‘disease activity score’and the number 28 refers to the 28 joints that are examined in thisassessment. In clinical practice a DAS28 score is typically assessed bycounting the number of swollen joints (out of the 28), counting thenumber of tender joints (out of the 28), taking blood to measure theerythrocyte sedimentation rate (ESR) or C reactive protein (CRP), usingquestionnaires (e.g. the HAQ which assesses function) and/or asking thepatient to make a ‘global assessment of health’ (indicated by marking a10 cm line between very good and very bad). These results are then fedinto a standardized mathematical formula to produce the overall diseaseactivity score. A DAS28 score of greater than 5.1 implies activedisease, less than 3.2 low disease activity, and less than 2.6remission. In a preferred embodiment, the present method achieves adecrease from baseline in DAS28 score of at least 1.0, e.g. at least1.05, at least 1.1, at least 1.15 or at least 1.2. In a particularlypreferred embodiment, the method achieves said reduction within e.g.10-24 weeks of treatment, within 12-20 weeks of treatment, or within14-18 weeks of treatment.

In a particularly preferred embodiment, the method achieves a reductionin the duration of morning stiffness. Said reduction is preferablyachieved within e.g. 10-24 weeks of treatment, within 12-20 weeks oftreatment, or within 14-18 weeks of treatment.

In a further particularly preferred embodiment, the method achieves areduction in mean swollen and tender and swollen joint count 66/68. The66/68 Joint Count evaluates 66 joints for swelling and 68 joints fortenderness and pain with movement. The total score is composed of pointsthat are based on the presence of pain and/or swelling in a joint. Saidreduction is preferably achieved within e.g. 10-24 weeks of treatment,within 12-20 weeks of treatment, or within 14-18 weeks of treatment.

In a further particularly preferred embodiment, the method achieves areduction in 28-joint count. The 28-Joint Count is another standardizedevaluation of involving examination of swelling of 28 specific joints.Said reduction in 28-joint count is preferably achieved within e.g.10-24 weeks of treatment, within 12-20 weeks of treatment, or within14-18 weeks of treatment.

In a further particularly preferred embodiment, the method achievesimprovement in one or more of Subject and Physician Global assessments,pain assessed by Visual Analogue Scale (VAS) and self-assessed physicaldisability (mHAQ). Said improvement is preferably achieved within e.g.10-24 weeks of treatment, within 12-20 weeks of treatment, or within14-18 weeks of treatment.

The method of the invention preferably comprises the administration tothe subject of a composition comprising rabeximod or a salt thereof,such as a composition as defined herein elsewhere, through the oral (orenteral) route of administration.

In particularly preferred embodiments of the invention, the treatmentcomprises the repeated oral administration of a composition containingrabeximod or a salt thereof, such as the oral solid composition asdefined herein, at a frequency of at least once every two days or atleast once every day. In preferred embodiments of the invention, thetreatment comprises the oral or enteral administration of a compositioncontaining rabeximod or a salt thereof, such as the oral solidcomposition as defined herein, every morning.

In particularly preferred embodiments of the invention, the treatmentcomprises the once daily administration of the composition.

In particularly preferred embodiments of the invention, the methodcomprises the administration of rabeximod at a daily dosage of at least1 mg, more preferably at least 2 mg, at least 4 mg, at least 6 mg, atleast 8 mg, at least 10 mg, at least 12 mg, at least 13 mg, at least 14mg, or at least 15 mg; or a salt of rabeximod in the equipotent dailydosage. In accordance with the various aspects of the invention, themethod comprises the administration of rabeximod at a daily dosage of500 mg or less, more preferably 250 mg or less, 100 mg or less, 75 mg orless, 50 mg or less, 40 mg or less, 30 mg or less, 25 mg or less or 20mg or less; or a salt of rabeximod in the equipotent dosage. Inparticularly preferred embodiments of the invention, the methodcomprises the administration of rabeximod in a daily dosage within therange of 5-25 mg, 10-20 mg, 12-18 mg, 13-17 mg, or 14-16 mg, e.g. about15 mg; or a salt of rabeximod in the equipotent dose. In certainpreferred embodiments, the method comprises the administration ofrabeximod at a daily dosage of 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or20 mg; or a salt of rabeximod at the equipotent daily dosage.

In particularly preferred embodiments of the invention, the methodcomprises the administration of rabeximod or a salt thereof in a dosageregime resulting in a minimal rabeximod plasma level, at steady-state,within the range of 25-150 ng/ml, preferably within the range of 30-125ng/ml, or within the range of 40-100 ng/ml. In particularly preferredembodiments of the invention, the method comprises the administration ofrabeximod or a salt thereof in a dosage regime resulting in a rabeximodplasma level, at steady-state, that is substantially within the range of25-150 ng/ml, preferably within the range of 30-125 ng/ml, or within therange of 40-100 ng/ml, throughout the dosing interval. In particularlypreferred embodiments of the invention, the method comprises theadministration of rabeximod or a salt thereof in a dosage regimeresulting in a rabeximod plasma level, at steady-state, that is withinthe range of 25-150 ng/ml, preferably within the range of 30-125 ng/ml,or within the range of 40-100 ng/ml, throughout the dosing interval.

In particularly preferred embodiments of the invention, the treatmentcomprises the repeated administration of the composition containingrabeximod or a salt, hydrate or solvate thereof, preferably inaccordance with the above-defined regimens, during a period of at least8 weeks, at least 12 weeks, at least 14 weeks, at least 16 weeks, atleast six months, at least nine months, at least one year, at least twoyears, at least three years, at least 5 years, or at least 10 years.There is no particular upper limit; treatment may be continued for aslong as it is deemed beneficial to the subject's overall health andwell-being (as can be determined by appropriately qualified healthcareprofessionals), e.g. for the rest of the subject's life.

In certain preferred embodiments of the invention, the present methodcomprises treatment with another medicament for treating rheumatoidarthritis. In preferred embodiments, such other medicament ismethotrexate, for instance administered orally or parenterally. Incertain preferred embodiments, a method as defined herein is provided,further comprising treatment with methotrexate, preferably comprisingthe administration of a stable dose of methotrexate, such as a weeklydose of 15-20 mg. The composition comprising rabeximod or a saltthereof, may be administered before, simultaneously or afteradministration of methotrexate.

In further aspects, the present invention relates to a compositioncomprising9-Chloro-2,3-dimethyl-6-(N,N-dimethylaminoethylamino-2-oxoethyl)-6H-indolo-[2,3-b]quinoxaline(Rabeximod) or a pharmaceutically acceptable salt thereof, preferably anoral solid composition as defined herein, for use in any of the methodsas defined here above.

In yet further aspects, the present invention relates to the use of acomposition comprising9-Chloro-2,3-dimethyl-6-(N,N-dimethylaminoethylamino-2-oxoethyl)-6H-indolo-[2,3-b]quinoxaline(Rabeximod) or a pharmaceutically acceptable salt thereof, preferably anoral solid composition as defined herein, for the manufacture of amedicament for use in any of the methods as defined here above.

Definitions/Misc

Further embodiments of the process are described in the experimentalsection herein, and each individual process as well as each startingmaterial constitutes embodiments that may form part of embodiments.

The term “treatment” and “treating” as used herein means the managementand care of a patient for the purpose of combating a condition, such asa disease or a disorder. The term is intended to include the fullspectrum of treatments for a given condition from which the patient issuffering, such as administration of the active compound to alleviatethe symptoms or complications, to delay the progression of the disease,disorder or condition, to alleviate or relief the symptoms andcomplications, and/or to cure or eliminate the disease, disorder orcondition as well as to prevent the condition, wherein prevention is tobe understood as the management and care of a patient for the purpose ofcombating the disease, condition, or disorder and includes theadministration of the active compounds to prevent the onset of thesymptoms or complications. The treatment may either be performed in anacute or in a chronic way. The patient to be treated is preferably amammal; in particular, a human being, but it may also include animals,such as dogs, cats, cows, sheep and pigs.

The term “and/or” as used herein is intended to mean both alternativesas well as each of the alternatives individually. For instance, theexpression “xxx and/or yyy” means “xxx and yyy”; “xxx”; or “yyy”, allthree alternatives are subject to individual embodiments.

As used herein “pharmaceutically acceptable additive” is intendedwithout limitation to include carriers, excipients, diluents, adjuvant,colorings, aroma, preservatives etc. that the skilled person wouldconsider using when formulating rabeximod in order to make apharmaceutical composition.

The adjuvants, diluents, excipients and/or carriers that may be used inthe composition of the invention must be pharmaceutically acceptable inthe sense of being compatible with rabeximod and the other ingredientsof the pharmaceutical composition, and not deleterious to the recipientthereof. It is preferred that the compositions shall not contain anymaterial that may cause an adverse reaction, such as an allergicreaction. The adjuvants, diluents, excipients and carriers that may beused in the pharmaceutical composition of the invention are well knownto a person within the art.

The above embodiments should be seen as referring to any one of theaspects (such as ‘solid oral composition comprising a crystalline formof Rabeximod’ and/or ‘solid oral unit dosage form, such as a capsule ortablet’) described herein as well as any one of the embodimentsdescribed herein unless it is specified that an embodiment relates to acertain aspect or aspects of the present invention.

All references, including publications, patent applications and patents,cited herein are hereby incorporated by reference to the same extent asif each reference was individually and specifically indicated to beincorporated by reference and was set forth in its entirety herein.

All headings and sub-headings are used herein for convenience only andshould not be construed as limiting the invention in any way.

Any combination of the above-described elements in all possiblevariations thereof is encompassed by the invention unless otherwiseindicated herein or otherwise clearly contradicted by context.

The terms “a” and “an” and “the” and similar referents as used in thecontext of describing the invention are to be construed to cover boththe singular and the plural, unless otherwise indicated herein orclearly contradicted by context.

Recitation of ranges of values herein are merely intended to serve as ashorthand method of referring individually to each separate valuefalling within the range, unless otherwise indicated herein, and eachseparate value is incorporated into the specification as if it wereindividually recited herein.

Unless otherwise stated, all exact values provided herein arerepresentative of corresponding approximate values (e.g., all exactexemplary values provided with respect to a particular factor ormeasurement can be considered to also pro-vide a correspondingapproximate measurement, modified by “about,” where appropriate).

All methods described herein can be performed in any suitable orderunless otherwise indicated herein or otherwise clearly contradicted bycontext.

The use of any and all examples, or exemplary language (e.g., “such as”)provided herein, is intended merely to better illuminate the inventionand does not pose a limitation on the scope of the invention unlessotherwise indicated. No language in the specification should beconstrued as indicating any element is essential to the practice of theinvention unless as much is explicitly stated.

The citation and incorporation of patent documents herein is done forconvenience only and does not reflect any view of the validity,patentability and/or enforceability of such patent documents.

The description herein of any aspect or embodiment of the inventionusing terms such as “comprising”, “having”, “including” or “containing”with reference to an element or elements is intended to provide supportfor a similar aspect or embodiment of the invention that “consists of”,“consists essentially of”, or “substantially comprises” that particularelement or elements, unless otherwise stated or clearly contradicted bycontext (e.g., a composition described herein as comprising a particularelement should be understood as also describing a composition consistingof that element, unless otherwise stated or clearly contradicted bycontext).

This invention includes all modifications and equivalents of the subjectmatter recited in the aspects or claims presented herein to the maximumextent permitted by applicable law.

The present invention is further illustrated by the following examplesthat, however, are not to be construed as limiting the scope ofprotection. The features disclosed in the foregoing description and inthe following examples may, both separately and in any combinationthereof, be material for realizing the invention in diverse formsthereof.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1: Mean plasma concentrations of Rabeximod (ng/mL) in patents withmoderate and severe rheumatoid arthritis following repeated once dailyoral administration of Rabeximod (in combination with a table dose ofmethotrexate) at week 12.

EXPERIMENTAL Process for Making Rabeximod.

The Starting materials: OXY001-01 has CAS number 49764-31-0 andOXY001-03 HCl has CAS number 4584-46-7.Starting materials: OXY001-01 and OXY001-03 HCl

TABLE A Overview Required Raw Materials and Quantities Quantity ItemDescription MW Mol required Eq. OXY001-01 281.74 46.3 13.0 kg 1.0OXY001-03 HCl 201.09 92.5 18.6 kg 2.0^(a) 50% NaOH aq. solution 40.00370.1 29.6 kg 8.0^(a) Potassium iodide, KI 166.00 37.5 6.2 kg 0.81^(a)Tetrahydrofuran, THF — — 705 L 54.2^(c) Potable water — — 395 L 30.4^(c)^(a)mol/mol of OXY001-01; b) kg/kg of OXY001-01; ^(c)L/kg of OXY001-01

TABLE B Raw/Intermediate Materials Specifications Item DescriptionParameter Method Specification OXY001-01 Appearance Visual Yellow toorange/brown solid ID NMR Conforms to structure Purity HPLC ≥80% Usetest HPLC ≥98% of OXY001 OXY001-03 HCl Appearance Visual White tooff-white solid ID NMR Conforms to structure Residual NMR To be reportedEtOAc Purity GC ≥90% 50% NaOH aq. Appearance Visual Colorless liquidsolution ID pH at 12-14 25° C. Assay — >31 w/w % from CoA Potassiumiodide, Appearance Visual Colorless to white solid KI ID EP ConformsAssay by — ≥95% from CoA titration Tetrahydrofuran, Appearance VisualColorless liquid THF ID NMR Conforms to reference Purity GC ≥99%Resulting Product: OXY001 Crude (crude rabeximod)Batch size: 11.38 kg of OXY001 CrudeProcess description: OXY001-01 (1.0 equivalent) was dissolved intetrahydrofuran (15.4 volumes) and 50% NaOH aqueous solution (8.0equivalents in relation to OXY001-01) in reactor (reactor was runningunder nitrogen at atmospheric pressure) and mixed at +55 to +60° C. upto approximately 1 hour until clear dark red solution was formed.Potassium iodide (0.81 equivalents) was added under vigorous stirringand mixed for 10 to 30 minutes at +55 to +60° C. OXY001-03 HCl (2.0equivalents) was added to the solution and mixed for at least 2 hours at+55 to +60° C. Following completion of the reaction, the mixture wasquenched with water (15.4 volumes) and tetrahydrofuran removed (15.4volumes) by evaporation under reduced pressure. The slurry was cooled to+20 to +25° C. and stirred for 1 hour and filtered with a Nutch filterusing Polyamide filter cloth (25 μm) or similar as filter media.Resulting cake was washed 3 times with water (3×5 volumes) until the pHof the filtrate was between 8-7 and dried on the filter at +40 to +45°C. for at least 12 hours by air suction and additionally in a vacuumtray dryer for 12 hours at +40° C. Afterwards resulting material wassuspended in in tetrahydrofuran (25 volumes) at +45 to +50° C. for atleast 1 hour. OXY001 Crude was isolated by filtration with a Nutchfilter using Polyamide filter cloth (25 μm) or similar as filter mediaand washed 2 times on the filter with tetrahydrofuran (2×7 volumes).Resulting cake was dried on the filter at +40 to +45° C. for at least 12hours and additionally in a vacuum tray dryer for 12 hours at +40° C.Theoretical yield: 18.96 kg

Yield: 60±5% (11.38±0.95 kg)

Maximum volume: 500 L

Purification of Crude Rabeximod:

OXY001 crude (1.0 equivalent) was dissolved in tetrahydrofuran (10volumes), water (3 volume), and 2M HCl (1.4 volumes) mixture. Thesolution was clear filtered and heated to +50° C. pH of mixture wasadjusted to 10-12 by addition of 2M NaOH (1.3 volume). The formed slurrywas cooled to +20 to +25° C. and diluted with water (12 volumes).

After stirring for at least 12 hours the slurry was filtered at +20 to+25° C. and washed on the filter with tetrahydrofuran:water (5:2)mixture (2×3 volumes). Rabeximod has a molecular weight of 409.92 g/moland is isolated as a crystalline free base having a melting point of259-261° C.

Process Description:

The micronisation operation is performed using a standard jet-mill. Theset point for the particle size was that not less than 90% of theparticles should be smaller than 10 μm. Inprocess samples were drawn andanalyzed using a Malvern Mastersizer during the process to verify that asufficient size reduction had been achieved (Malvern Mastersizer 2000instrument, equipped with a Scirocco 2000(A) dispersion unit and a MicroTray, operated at an air pressure of 2.5 bar, a feed rate of 60%, ameasuring time of 5 seconds and a background time of 5 seconds;compliant with Ph.Eur method 2.9.31).

Results of the micronisation step in particle size is provided in

Table 1 for Rabeximod drug substance batches.

TABLE 1 Particle size results following micronisation of Rabeximod drugsubstance batches Feed Batch particles Result after micronisation BatchNo. size % <10 μm D(0.1) D(0.5) D(0.9) % <10 μm 146-32  20 g 41.9% 0.7μm 2.2 μm 8.2 μm 98.1% 149 5902 g 30.9% 0.6 μm 2.0 μm 5.9 μm 99.1% 1531015 g 32.7% 0.6 μm 1.9 μm 5.7 μm 99.1% 262-1¹ 3430 g 29.0% 0.7 μm 2.2μm 8.4 μm 94.5% 262-2¹ 3640 g 32.6% 0.7 μm 2.2 μm 7.6 μm 92.6% ¹The bulkbatch was divided into two separate micronisation runs.

Rabeximod Drug Product

The batch formula for the different strengths is depicted in Table 2.

TABLE 2 Composition Rabeximod Drug Product of the following strengths6.25, 12.5, 15, 25 or 50 mg Quantity (mg) Name of 6.25 12.5 25 50Reference To Ingredients mg mg 15 mg mg² mg² Function Standards Activesubstance Rabeximod¹ 6.25 12.5 15 25 50 Active In-house substancespecifications Excipients Microcrystalline 211.55 205.3 202.8 — — FillerPh. Eur. cellulose (Avicel PH-102) Microcrystalline — — 165 140 FillerPh. Eur. cellulose (Avicel PH-200) Silica colloidal — — 6 6 Glidant Ph.Eur. anhydrous (Aerosil 200) Magnesium 2.2 2.2 2.2 4 4 Lubricant Ph.Eur. stearate Capsule Gelatine capsules 1 ea 1 ea 1 ea 1 ea 1 ea —In-house Size 1 Swedish orange ¹If the API (rabeximod) purity is lowerthan 98.0% the master formula unit is corrected accordingly (for API andMicrocrystalline Cellulose). ²To improve the flow characteristics forthese two high doses the concentrations of the lubricant and magnesiumstearate were increased and silica colloidal added.

Process Description

The required quantity of microcrystalline cellulose was weighed andsplit into two equal portions. First portion of microcrystallinecellulose followed by the entire amount of Rabeximod drug substance waspassed through a nominal 1000 μm screen and transferred directly insidean appropriate sized blending bin having a capacity such that (total)powder fill is between 33% and 66% of blending bin volume. The secondportion of microcrystalline cellulose (and silica colloidal ifapplicable) was passed through a nominal 1000 μm screen and transferreddirectly inside the same blending bin. The mixture was blended atappropriate speed and time to make a uniform distribution, such as 17rotations per minute (RPM) for about 20 min at following room conditions+15 to +25° C. and 35 to 65% RH (Relative Humidity). Optional sampleswere taken after 15 and 20 minutes to assess blend homogeneity. Theamount of magnesium stearate was passed through a 700 μm nominal screeninto the blending bin. The mixture was blended for at appropriate speedand time to make a uniform distribution, such as 17 RPM for at least 3min followed by sampling (10 samples: 3× top, 4× middle, and 3× bottom)to determine blend homogeneity (acceptance criteria: average of 10content samples between 95.0-105.0% of label claim with RSD≤5.0%).Blended mixture was transferred to double polyethylene bags in a rigidHigh Density Poly Ethylene (HDPE) container. Following acceptable blendcontent homogeneity, the mixture was processing further in a capsulefilling equipment at a target weight of 220 mg per capsule (or 200 mgfor 25/50 mg strengths). Thereafter from the accepted capsules therequired samples were taken for release testing, stability, and retainand subsequently stored in double polyethylene bags in a rigid HDPEplastic container before packaging (current configuration is a blister,previously HDPE bottle).

Current packaging configuration is an appropriate blister pack such asan opaque, white 250 μm Polyvinylchloride (PVC) with 40 grams per squaremeter (gsm) Polyvinylidene chloride (PVdC) (Duplex) laminate heat sealedto 20 μm aluminium foil. Each blister pack contains multiple capsulessuch as 18 capsules.

Batch release results of batches used in Phase 2 and Phase 1 clinicalstudies are provided in Table 3 and Table 4, respectively.

The drug substance is virtually immediately released from theformulation with >90% released after 45 minutes. During the developmentof the formulations containing 12.5 mg, 25 mg, and 50 mg for theclinical phase study it was shown that for all three strengths more than90% of the drug substance was already released after 15 minutes. Inconclusion the capsules meet the requirements for conventional-releasedosage forms in Ph. Eur. and immediate release dosage forms in USP.

TABLE 3 Batch release results of Rabeximod drug product batches used inPhase 2 clinical study 6.25 mg 12.5 mg 15 mg 25 mg Capsule StrengthClinical Clinical Clinical Clinical Use of Batch Phase II Phase II PhaseII Phase II Test Specification Results Appearance Yellow powder CompliesComplies Complies Complies contained in a size 1 Swedish orange hardgelatine capsule Assay (High 90.0-110.0% of label 101.1% 100.3% 101.9%99.1% Performance Liquid strength (LS) Chromatography (HPLC))Identification The retention time of the Complies Complies CompliesComplies (HPLC) main peak in the sample chromatogram corresponds to thatof the main peak in the standard chromatogram Related Substances ≤1.0%w/w Complies Complies Complies Complies (HPLC) To be reported RRT % RRT% RRT % RRT % Largest impurity Relative retention w/w w/w w/w w/w Numberof time (RRT) 1.16 1.16 1.16 1.16 impurities >0.05% 0.06 0.06 0.07 0.07w/w 1.36 1.35 1.36 1.35 0.08 0.09 0.08 0.09 Total = Total = Total =Total = 0.14% w/w 0.15% w/w 0.15% w/w 0.16% w/w Sum of ≤2.0% w/w No NoNo No impurities >0.1% impurity >0.1% impurity >0.1% impurity >0.1%impurity >0.1% w/w w/w w/w w/w w/w Dissolution Not less than 70% @ 4596.6% 99.3% 98.7% 97.2% mins Content Uniformity ≤L1 (15.0) AV₍₁₀₎ =AV₍₁₀₎: AV₍₁₀₎ = AV₍₁₀₎: Stage 1 ≤L2 (25.0) and no 5.1 1.6 1.9 4.3acceptance value individual content for (AV) Rabeximod in the Stage 2dosage unit is less than acceptance value (1 − L2 × 0.01)M nor more (AV)than (1 + L2 × 0.01)M Microbial Limit Total bacteria not more 25 CFU/g<10 CFU/g <10 CFU/g. <10 CFU/g Test Total Viable than 1000 ColonyForming 10 CFU/g <10 CFU/g <10 CFU/g <10 CFU/g Aerobic Unit (CFU)/g.Absence Absence Absence Absence Count Total fungi not more confirmedconfirmed confirmed confirmed Absence of than 100 CFU/g Escherichia-coliAbsence of Escherichia- coli confirmed

TABLE 4 Batch release results of batches used in Phase 1 clinical studyCapsule Strength 12.5 mg 50 mg Use of Batch Clinical Clinical TestSpecification Phase 1 Phase 1 Appearance White/opaque white CompliesComplies gelatine capsule containing yellow powder Assay (HPLC)90.0-110.0% of LS 98.5% 96.2% Identification Conforms to standardComplies Complies (HPLC) chromatogram Related Read and record RRT % w/wRRT % w/w Substances 0.85 0.05 0.85 0.05 (HPLC) 0.91 0.10 0.90 0.09 0.92 <LOQ¹ 0.92 <LOQ 0.93 0.05 0.94 0.05 0.97 <LOQ 0.97 <LOQ 1.09 <LOQ 1.08<LOQ 1.11 0.06 1.11 0.07 Total 0.26 Total 0.26 Dissolution (HPLC) NLT70% of label strength 98.0% @ 45 min 97.0% @ 45 min @ 45 min ContentUniformity 85-115% of label 97.5% 95.2% (HPLC) strength [% RSD₁₀ = 2.8%][% RSD₁₀ = 2.1%] [% RSD ≤6%] ¹Limit of Quantification

Phase 1 Clinical Trial

The Phase 1 study assessed the safety, tolerability, pharmacokineticsand pharmacodynamics of single and multiple oral rising doses ofRabeximod (in a capsule formulation) in healthy male volunteers. Thestudy also included an open-label, randomised, two-period crossover partthat was designed to investigate the effect of food on thepharmacokinetics of Rabeximod. In total, 87 healthy male subjects wereenrolled into the study.

Results demonstrated that Rabeximod was well tolerated at single dosesup to 400 mg. Multiple oral doses up to a 200 mg loading dose followedby 50 mg maintenance dose were also well tolerated. Higher doses: singledose of 600 mg, and multiple dose of 600 mg loading followed by 100 mg,were less well tolerated due to phototoxicity reactions.

Phase II Clinical Trial

The Phase II study was a randomised, parallel-group, double-blind,dose-ranging, placebo-controlled study of Rabeximod in patients withmoderate or severe active RA with an inadequate response tomethotrexate. The aim of the study was to evaluate the efficacy andsafety of Rabeximod administered at doses of 6.25, 15 and 37.25 mgorally once daily for 12 weeks in combination with methotrexate.

Study Objectives

The primary objective of this study was to evaluate the efficacy(American College of Rheumatology 20) of Rabeximod administered orallyonce daily for 12 weeks in combination with a stable dose ofmethotrexate in patients with moderate or severe active rheumatoidarthritis. Efficacy was evaluated by American College of Rheumatology 20(66/68 joint count) after 12 weeks of treatment.

Secondary objectives were to:

-   -   Evaluate additional efficacy parameters of Rabeximod after 4, 8        and 12 weeks of treatment.    -   Evaluate the safety of Rabeximod administered orally once daily        for 12 weeks in combination with a stable dose of methotrexate        in patients with moderate or severe active rheumatoid arthritis.    -   Evaluate patient functional disability status using the modified        Health Assessment Questionnaire.    -   Evaluate the pharmacokinetics of Rabeximod when administered        with a stable dose of methotrexate.    -   Evaluate correlation between plasma concentration and effect at        Week 12.    -   Evaluate the pharmacodynamic effect of Rabeximod when        administered with a stable dose of methotrexate.

The primary endpoint of this study is the American College ofRheumatology (ACR20) 20 improvement measured after 12 weeks of treatmentwith study drug. The ACR20 is a composite score defined as animprovement of 20% in the number of swollen and tender joints and a 20%improvement in 3 of the following 5:

-   -   Patient self-assessed disability by modified Health Assessment        Questionnaire (mHAQ)    -   Physician Global assessment    -   Subject Global assessment    -   Patient pain assessment    -   Acute phase reactant (C-reactive protein [CRP])        Secondary efficacy endpoints were as follows:    -   ACR20 improvement measured after 4 and 8 weeks of treatment    -   Subgroup analysis of ACR20 results from patients enrolled with        baseline CRP >1.5 mg/dL.    -   ACR50/70 improvement measured after 4, 8 and 12 weeks    -   Original Disease Activity Score (DAS) change from baseline        (according to the European League Against Rheumatism [EULAR]        Response Criteria). Note: the Original DAS was replaced with        DAS28    -   Change from baseline in: number of swollen/tender joints,        morning stiffness duration. Subject and Physician Global        assessments, pain assessed by Visual Analogue Scale (VAS),        self-assessed physical disability (mHAQ), erythrocyte        sedimentation rate (ESR) and CRP    -   The evaluation of pharmacokinetic (PK) and pharmacodynamic (PD)        high sensitive CRP, TNF-a, interleukin-6 [IL-6] and anti-cyclic        citrullinated peptide antibody [anti-CCP]) over time

Study Design

This was a multicentre, multinational, dose-ranging, randomised,double-blind, multiple dose, placebo-controlled, parallel-group study ofRabeximod administered orally in a total of 225 enrolled patients withmoderate or severe active RA. All patients must have been receivingweekly methotrexate treatment for at least 16 weeks (with unchangeddoses for at least 8 weeks) up to Day 0 of study.

Diagnosis of RA was based on the American Rheumatism Association (ARA)1987 revised criteria, having an ACR global functional class of 1 to 3,stable methotrexate dose of at least 15 mg per week and centrallaboratory CRP level at study entry of at least 1.5 mg/dL and clinicalfindings of active disease (at least 6 swollen and 6 tender joints topalpation). Individual patient duration in the study was approximately126 days (a 14-day screening period, an 84-day treatment period [12weeks], and a 28 day [4-week] follow-up period).

After meeting the inclusion and exclusion criteria and providinginformed consent, patients were randomly assigned (1:1:1:1 ratio) toreceive 1 of the following treatments:

-   -   6.25 mg Rabeximod    -   15 mg Rabeximod    -   37.5 mg Rabeximod    -   Placebo

A total of 9 visits occurred over the course of the study (screening,randomisation [Day 0, baseline]. Day 1, and Weeks 2, 4, 6, 8, 12 and16). The Day 1 visit was included for a subgroup of 36 patients (PK/PDsubgroup) who were selected at specified study centres to alsoparticipate in the PK/PD aspect of the study. Individual patientduration in the study was approximately 126 days (a 14 day screeningperiod, an 84 day treatment period [12 weeks], and a 28 day [4 week]follow-up period).

Efficacy assessments included swollen and tender joint counts (66/68joint count), morning stiffness, Subject and Physician Globalassessments, pain assessments, self-assessed physical disability, ESR,CRP measurements, and the mHAQ. Safety assessments included AEs, vitalsigns, weight, physical examination, 12-lead ECG and safety laboratorytests (serum chemistry, haematology and urinalysis).

In addition to standard efficacy and safety assessments, it was plannedthat 40 patients in selected study centres would have blood draws at thebeginning of the study (Day 1) and at the end of the study (Week 12) toassess the PK of Rabeximod. The actual number of patients whoparticipated in the PK aspect of the study was 36. The ACR20, ACR50 andACR70 are assessments of RA improvement. The mHAQ is a validatedinstrument used to assess patient satisfaction in activity of dailyliving. It was planned to use the Original DAS as the outcome measure,but this was replaced with DAS28 because it is used more frequently intherapeutic studies have been used in many RA studies.

Study Population

Male or female patients who met all of the following criteria wereeligible for participation in the study:

-   -   1. >18 years old.    -   2. Diagnosed with RA based on the ARA 1987 revised criteria at        least 16 weeks prior to study enrolment. Day 0.    -   3. An ACR global functional status class of 1 to 3.    -   4. Active disease, defined as the presence of 6 swollen joints        and 6 tender joints in a 44 joint examination.    -   5. C-reactive protein level at screening of 1.5 mg/dL.    -   6. Had been taking oral or parenteral methotrexate (15 mg weekly        or above), had been using methotrexate for at least 16 weeks (up        to Day 0), and had been on a stable dose for at least 8 weeks,        up to Day 0 (patients using 10 to 15 mg methotrexate may have        been considered for inclusion if an unacceptable toxicity was        recorded when higher doses were used).    -   7. Stable optional RA medication:        -   a. Folic acid supplementation if already in use        -   b. Nonsteroidal anti-inflammatory drugs including            cyclooxengase-2 (Cox-2) inhibitors—doses must have been            stable for 4 weeks prior study enrolment (Day 0) with study            drug and consistent with labelling recommendations        -   c. Acetylsalicylic acid was allowed in low doses as            cardiovascular prophylaxis        -   d. Oral glucocorticoids; daily doses of up to 10 mg            (inclusive) of prednisolone or equivalent for 4 weeks prior            study enrolment (Day 0) with study drug        -   e. Painkillers (acetaminophen. Tramadol and similar, alone            or in combinations) usage as per routine instructions was            allowed, except for 24 hours before rheumatology            evaluations.    -   8. Where using adequate forms of birth control—defined as 2        methods of birth control (e.g., contraceptive pill and        single-barrier method). Birth control was not necessary in        patients who has been postmenopausal for >1 year or who were        surgically sterile (including hysterectomy).    -   9. Patients must have been able to give informed consent after        reading and understanding the patient information sheet, and        willing to comply with all study procedures including completing        all questionnaires.        Patients who met any of the following criteria were not included        in the study:    -   1. Arthritis onset prior to 16 years old.    -   2. Any of the following infections:        -   a. Known or acute infection that may have affected CRP            levels        -   b. Active tuberculosis        -   c. Known chronic infection with human immunodeficiency virus            (HIV), hepatitis C virus (HCV) or hepatitis B virus (HBV)            including positive serology.    -   3. Ongoing systemic inflammatory condition which may have        interfered with the results of clinical or laboratory tests        planned in the study (e.g., systemic lupus erythematosus or any        other systemic rheumatic disease other than RA).    -   4. Any clinically significant concurrent medical condition        resulting in the following abnormal laboratory values:        -   a. Hepatic            -   i. Aspartate aminotransferase (AST) >2× the upper limit                of normal (ULN)            -   ii. Alanine aminotransferase (ALT) >2×ULN            -   iii. Alkaline phosphatase >2.5×ULN            -   iv. Total bilirubin >ULN.        -   b. Renal            -   i. Serum creatinine >1.5×ULN            -   ii. Urea >1.5×ULN            -   iii. Significant proteinuria (2+ on urinary dipstick                test).        -   c. Haematology            -   i. Haemoglobin (HGB)<9 g/dL            -   ii. Leukocytes <3.5×10{circumflex over ( )}/dL            -   iii. Absolute neutrophil count (ANC)<1.5×10{circumflex                over ( )}/L            -   iv. Platelets <100×10{circumflex over ( )}/L.    -   5. Present or previous malignancies, except history of cured        squamous or basal skin cell carcinoma.    -   6. Uncontrolled diabetes mellitus.    -   7. Any medical condition, which in the judgment of the        Investigator, put the patient at an unacceptable risk by        participating in the study.    -   8. Required 1 or several of the following medications:        -   a. Narcotics (except for Tramadol) or any drug for treatment            of RA other than NSAIDs, Cox-2 inhibitors,            acetaminophen/paracetamol for pain and arthritis control, or            aspirin (except for cardiovascular prophylaxis)        -   b. Current or previous use of biological anti-inflammatory            or immune-modulatory therapy for treatment of RA (e.g.,            anti-IL-1 and anti-B-cell treatment)        -   c. Current or previous use of DMARDs (e.g., sulphasalazine,            antimalarials, etc.), except methotrexate, within 4 months            prior to study enrolment (Day 0)        -   d. Anti-tumour necrosis factor [anti-TNF] 2 months prior to            study enrolment (Day 0)        -   e. Intra-articular, intramuscular (i.m.), or intravenous            (i.v.) glucocorticoids within 4 weeks prior to study            enrolment (Day 0).    -   9. Participation in an investigational study within the past 30        days or expected to be treated with an investigational product        during this study period.    -   10. Current or recent history (within 12 months of screening) of        drug or substance abuse, including alcohol.    -   11. Females who were pregnant or nursing.    -   12. Any clinically significant abnormality on physical        examination, laboratory testing, vital signs, or 12-lead ECG        suggestive of a significant unstable medical condition.    -   13. Any other condition that, in the opinion of the        Investigator, could have interfered with the patient's study        participation.

Test Drug Formulation

Rabeximod was supplied as size 1, Swedish orange gelatine capsules, inmicrocrystalline cellulose and magnesium stearate, which were producedaccording to the process described here above. Placebo was supplied assize 1, Swedish orange gelatine capsules, in microcrystalline celluloseand magnesium stearate, with no active ingredient Rabeximod. Placebocapsules were identical in appearance to the test drug formulation.Capsules for all treatment arms were supplied in blisters of identicalappearance.

Selection and Timing of Dose for Each Patient

The selection of dose for each patient (6.25 mg Rabeximod, 15 mgRabeximod, 37.5 mg Rabeximod or placebo) was determined by randomassignment. The study drug was to be taken at approximately the sametime every morning, starting from Day 1. For the PK/PD subgroup, on theday when the PK/PD sampling was scheduled, study drug was to be takenafter the first blood sampling. The study design of the treatment phasewas double-blind. All study drug, including placebo, were identical insize, shape, colour and taste, thus allowing double-blind conditions tobe maintained. All study personnel and patients remained blinded to thedrug treatment assignments. Patients self-administered all doses ofstudy drug end were instructed to return all residual, unused and emptypackaging to the clinic at scheduled visits. If dosing compliance wasnot maintained at between 80% and 120% then the patient was to bewithdrawn from the study. Patients in the PK/PD subgroup were to takestudy drug at the clinic on Day 1 and at Week 12. Compliance wasmonitored through drug accountability. The Investigator, or designee,maintained an inventory record of study drug received, dispensed,administered and returned to assure the Sponsor that study drug was notdispensed to any person who was not a patient under the terms andconditions set forth in the protocol. Clinically significant protocoldeviations were identified based on criteria determined by the projectleader to be clinically relevant. Deviations were reported on the CRFs.Additionally, upon completion of the study, certain deviations (e.g.,visit window deviations) were identified through the use of SAS®programming.

Pharmacokinetics

The PK assessment of Rabeximod was performed in a subgroup of 36patients during the study.

Concentration-time profiles for plasma Rabeximod following single(Day 1) and repeated administration (Week 12) of Rabeximod weredetermined. Results are summarized in the following Table 5.

TABLE 5 Summary of Pharmacokinetic Parameters by Visit (PK Population)6.35 mg 15 mg 37.5 mg (N = 9)² (N = 11) (N = 8) C_(max) (μg/mL) Day 1, n8 10 8 Median 7.05 16.0 41.8 Min, Max 4.41, 21.8 12.5, 37.5 25.3, 66.3Geometric mean¹ 7.92 18.3 41.7 Week 12, n 7 11 4 Median 37.5 91.6 238.0Min, Max 11.0, 95.1 44.3, 134  140.0, 314.0 Geometric mean¹ 31.0 79.7218.0 T_(max) (hours) Day 1, n 8 10 8 Median 8.03 6.04 5.03 Min, Max5.92, 24.0 1.98, 24.0 2.0, 8.0 Week 12, n 7 11 4 Median 2.17 4.0 3.99Min, Max  0.0, 48.1  0.0, 12.0 3.95, 4.08 AUC_(0-t) (hr*ng/mL) Week 12,n 7 11 4 Median 2810.0 5590.0 17500.0 Min, Max  631.0, 10100.0  2140.0,10300.0 8460.0, 25400.0 Geometric mean¹ 2530 4970.0 15900.0 AUC_(0-τ)(hr*ng/mL) Day 1³, n 8 10 9 Median 107.0 254.0 697.0 Min, Max  77.3,197.0 161.0. 547.0 374.0, 1070.0 Geometric mean¹ 112.0 282.0 689.0 Week12, n 7 7 4 Median 710.0 1480.0 4540.0 Min, Max  178.0, 2090.0  795.0,2530.0 2230.0, 5990.0 Geometric mean¹ 587.0 1530.0 4040.0 T_(1/2)(hours) Week 12, n 7 11 4 Median 86.6 77.6 107.0 Min, Max  49.4, 199.0 37.1, 154.0  83.5, 154.0 Geometric mean¹ 81.5 77.1 111.0 MTX:methotrexate; C_(max): maximum observed plasma concentration; SD:standard deviation; T_(max): time of occurrence of C_(max); AUC_(0-τ):area under the concentration versus time curve within a dosing interval;AUC_(0-t); area under the concentration versus time curve to the lastmeasurable time point; T_(1/2): apparent terminal half-life; min:minimum; max: maximum ¹Geometric coefficient of variation =(sqrt(exp(SDln{circumflex over ( )}2) − 1))*100 ²Patient 21-018 wasmistakenly thought to have received placebo; samples were not analysedfor Rob 803 as a result. ³AUC_(0-τ) is equivalent to AUC_(0-t) on Day 1.

Following a single administration of Rabeximod at 6.25, 15 and 37.5 mgin combination with a stable dose of methotrexate, C_(max) of Rabeximodwere attained (T_(max)) at approximately 5 to 8 hours post-dose acrossall dose levels (median estimates). However, following repeatedadministration during Week 12, C_(max) was attained earlier atapproximately 2 to 4 h post-dose (median estimates). Plasmaconcentrations of Rabeximod declined during Week 12 (FIG. 1) withgeometric mean apparent terminal half-lives (t_(1/2)) of 81.5, 77.1 and111 hours following administration at Rabeximod 6.25, 15 and 37.5 mg,respectively.

Rabeximod terminal half-lives were 81.5, 77.1 and 111 hours followingadministration at 6.25, 15 and 37.5 mg, respectively. The observedgeometric mean values for AUC_(0-τ), AUC_(0-t) and C_(max), increased inan approximately dose-proportional manner over the dose range of 6.25 to37.5 mg when administered in combination with a stable dose ofmethotrexate.

Methotrexate does not appear to have an impact on the kineties ofRabeximod.

Efficacy

An assessment of tender and swollen joints was performed for the ACRresponse criteria. Joints to be evaluated for disease activityassessment (using the ACR 66/68 joint count) included the following:temporomandibular, sternoclavicular, acromioclavicular, shoulder, elbow,wrist, all 5 metacarpophalangeal joints, 4 proximal interphalangealjoints, 4 distal interphalangeal, thumb interphalangeal joint, hip (fortenderness only), knee, ankle, tarsus, 5 metatarsophalangeal, 4 proximalinterphalangeal and foot thumb interphalangeal joints at each side. Inaccordance with the protocol, an independent joint reviewer performedthe rheumatology examination, where possible. If an independent jointreviewer was not available, the same examiner performed all rheumatologyexaminations for a patient throughout the study.

Patient satisfaction in performing activities of daily living wasassessed using the mHAQ. The mHAQ included questions concerning theperceived patient satisfaction in various activities of daily living:arising, dressing and grooming, eating, walking, hygiene, reach, gripand 3 specific daily activities (run errands, get in and out of car, dochores). Also, aids or devices used and help from another person neededto perform any of the activities were captured. Patients ratedactivities by difficulty level, ranging from the ability to complete theactivity ‘without any difficulty’ to ‘unable to perform’ a specificactivity. Higher numbers indicated more difficulty performing theactivities. Patient self-assessed physical disability was calculated asDisability Index (DI).

Physician Global assessment of overall disease activity occurred aspresented in the schedule of events (Table 1). Physicians assessed eachpatient's overall disease activity by making a mark on a 100 mm VAS. Thelow end of the scale indicated ‘no symptoms’ and the high end indicated‘very severe’. Physicians were asked to mark the VAS based on thefollowing instruction: “Make a mark on the line indicating yourassessment of the patient's overall disease activity.” This assessmentwas completed after the joint assessment.

Subject Global assessment of the impact of their arthritis occurred aspresented in the schedule of events (Table 1). Patients assessed theimpact their Arthritis by making a mark on a 100 mm VAS. The low end ofthe scale indicated ‘no impact’ and the high end indicated ‘verysignificant impact.’ Patients were asked to mark the VAS according tothe following question: “Considering all of the ways your arthritisaffects you, mark ‘x’ on the scale for how well you are doing”. This VASvalue was also used for the calculation of DAS28 and ACR20/50/70.

Patient pain assessment occurred as presented in the schedule of events(Table 1). Patients assessed the pain associated with their Arthritis bymaking a mark on a 100 mm VAS. The low end of the scale indicated ‘nopain’ and the high end indicated ‘very severe pain’. Patients were askedto mark the VAS based on the following question: “How much pain have youhad because of your illness in the past week.”

Blood was drawn to evaluate ESR and CRP as presented in the schedule ofevents (Table 1). An ESR tube containing anticoagulated blood was placedupright in a tube, for-purpose rack. C-reactive protein was measured bythe central laboratory using high sensitivity methodology.

The Original DAS was to be assessed as presented in the schedule ofevents (Table 1); further information on Original DAS is provided in theProtocol. However, as DAS28 is a more frequently used outcome measure intherapeutic studies. Original DAS was replaced with DAS28. The DAS28-ESRwas based on an external standard of RA disease activity and combinedinformation from a swollen/tender 28 joint count, ESR, and a generalhealth (GH) assessment on a VAS. For the 28 joint count, the followingjoints were assessed: shoulders, elbows, wrists, metacarpophalangealjoints, proximal interphalangeal joints, and the knees, at each side. Inaddition, the patient's GH measured on a VAS of 100 mm (both are useablefor this purpose) was obtained. The DAS28 had a continuous scale rangingfrom 0 to 10. The level of disease activity could be interpreted as low(DAS28<3.2), moderate (3.2<DAS28<5.1) or high (DAS28>5.1). A patient wasconsidered to be in remission if they have a DAS28 lower than 2.6.

Morning stiffness was assessed by having the patient answer thefollowing question: “On average, how long does it take for your morningstiffness to resolve?” The answer was recorded in minutes.

Patients who received Rabeximod (plus methotrexate) experienced agreater improvement in symptoms with onset starting at least 8-12 weeksafter the first dose, with further improvement noted during follow-up(Week 16) compared with patients who received placebo (plusmethotrexate). At week 12, a larger proportion of patients in theRabeximod groups achieved ACR20 compared with patients in the placebogroup. The proportions of patients achieving ACR20 in the Rabeximodgroups continued to increase at Week 16, with the best results in theRabeximod 15 mg group.

Similar results were observed for ACR50. At Week a higher percentage ofpatients in the Rabeximod 6.25, 15, and 37.5 mg groups achieved an ACR50response, respectively, compared with the placebo group, with the bestresults in the Rabeximod 15 mg group. The increases in the proportionsof patients achieving ACR50 were greater at Week 16.

DAS28 mean baseline scores for each treatment group was very high,indicating a high disease activity in the study population. For theRabeximod groups there was a gradual decrease (improvement) in meanDAS28 score from baseline during the study, with better responsesobserved at Weeks 12 and 16 compared with placebo; at Week 12 changes inmean DAS28 scores were −1.063, −1.214 and −1.204 points in the Rabeximod6.25, 15 and 37.5 mg groups, respectively, compared with −0.983 point inthe placebo group.

The percentage of patients achieving a good or moderate EULAR responserate gradually increased during the study, reaching 37.8, 67.7 and 55.8%in the Rabeximod 6.5, 15 and 37.5 mg groups, respectively, compared with38.5% in the placebo group at Week 16.

For the Rabeximod groups, there was a notable decrease (improvement)from baseline in each separate component of the ACR response: the meanswollen and tender and swollen joint count 66/68, Subject and PhysicianGlobal assessments of disease activity (VAS), joint pain, HAQ-DI, acutephase reactants (CRP and ESR).

There were greater reductions (improvement) in the duration of morningstiffness for the Rabeximod groups compared with placebo at the majorityof time points, with the best results seen in the Rabeximod 15 mg group,especially at week 16. Percentage mean reduction from baseline in jointpain was notable at week 1, with best results seen in the Rabeximod 15mg group. At Week 16, notable improvements in percentage mean reductionfrom baseline in swollen (66) and tender (68) joint counts, Physicianand Subject Global assessments of disease activity were observed, withbest results seen in the Rabeximod 15 mg group.

Safety

Safety measurements for this study included AEs, clinical laboratorytests, physical examinations, vital signs and resting 12-lead ECGs.

Rabeximod, administered once daily at 6.25, 15 and 37.5 mg waswell-tolerated in RA patients taking methotrexate. No deaths occurredduring the study. Overall, 96 patients (42.7%) experienced at least 1TEAE during the study, 65 (28.9%) of whom experienced at least 1 TEAEwhich was considered related to study drug. The proportion of patientsexperiencing study drug-related AEs was greater in the Rabeximod groups(34.5%; pooled) than in the placebo group (11.1%), with the majority ofthese events occurring in the Rabeximod 37.5 mg group (32 patients[58.2%]). Overall, the majority of events were mild or moderate inseverity.

The majority of changes in physical examinations that occurred duringthe study were skin abnormalities, all of which occurred in theRabeximod group and most of which were reported as AEs. These eventsclearly demonstrate a dose response as the majority of events werereported in the Rabeximod 37.5 mg group, followed by the Rabeximod 15 mggroup and then the Rabeximod 6.25 mg group.

Overall, there were no notable changes in vital signs and 12-lead ECGsover the course of the study.

1. A method of treating a human subject suffering from and/or diagnosedwith rheumatoid arthritis, said method comprising the oraladministration to said subject, of a composition comprising9-Chloro-2,3-dimethyl-6-(N,N-dimethylaminoethylamino-2-oxoethyl)-6H-indolo-[2,3-b]quinoxaline(rabeximod) or a pharmaceutically acceptable salt thereof, wherein themethod comprises the oral administration of rabeximod at a daily dosagewithin the range of 1-50 mg, or the oral administration of a salt ofrabeximod at the equivalent daily dosage.
 2. The method according toclaim 1, wherein the method comprises the oral administration ofrabeximod at a daily dosage within the range of 1-40 mg, or the oraladministration of a salt of rabeximod at the equivalent daily dosage. 3.The method according to claim 1, wherein the method comprises the oraladministration of rabeximod at a daily dosage within the range of 5-25mg, or the oral administration of a salt of rabeximod at the equivalentdaily dosage.
 4. The method according to claim 1, wherein the methodcomprises the administration of rabeximod or a salt thereof in a dosageregime resulting in a rabeximod plasma level, at steady-state, that iswithin the range of 25-150 ng/ml throughout the dosing interval.
 5. Themethod according to claim 1, wherein the composition comprisingrabeximod is a solid unit dosage form suitable for oral administration,preferably a filled capsule, comprising rabeximod in micronized form. 6.The method according to claim 1, wherein the method is a method oftreating rheumatoid arthritis, delaying the progression of rheumatoidarthritis, stopping or preventing the progression of rheumatoidarthritis, inducing remission of rheumatoid arthritis, delaying theonset of rheumatoid arthritis or preventing the onset of rheumatoidarthritis.
 7. The method according to claim 1, wherein the method is amethod of treating a symptom of rheumatoid arthritis, delaying theprogression of a symptom of rheumatoid arthritis, stopping or preventingthe progression of a symptom of rheumatoid arthritis, inducing remissionof a symptom of rheumatoid arthritis, de-laying the onset of a symptomof rheumatoid arthritis or preventing the onset of a symptom rheumatoidarthritis, and wherein the symptom is selected from the group consistingof tender, warm and/or swollen joints; joint stiffness, particularly inthe morning and after periods of inactivity.
 8. The method according toclaim 1, wherein the subject is a poor responder to treatment withmethotrexate.
 9. The method according to claim 1, wherein the subject tobe treated is a human subject suffering from rheumatoid arthritis ofglobal functional status class of II, III or IV, preferably III or IV.10. The method according to claim 1, wherein the method achieves one ormore of an ACR20 response, a reduction in the duration of morningstiffness and a reduction in mean swollen and tender and swollen jointcount 66/68.
 11. The method according to claim 10, wherein the methodachieves one or more of an ACR20 response, a reduction in the durationof morning stiffness and a reduction in mean swollen and tender andswollen joint count 66/68, within a period of 14-18 weeks.
 12. Themethod according to claim 1, wherein the method comprises the repeatedadministration of the composition containing rabeximod or a saltthereof, during a period of at least 12 weeks, preferably at least 16weeks.
 13. The method according to claim 1, wherein, the method furthercomprises treatment of the subject with methotrexate.